Anticoagulation of blood is necessary for prevention of clotting and/or thromboembolism during cardiopulmonary bypass or other procedures that require extracorporeal circulation. Conventionally, anticoagulation is achieved by administering heparin and reversed by neutralizing heparin with protamine. Both of these procedures may have potential pathological consequences. A subpopulation of patients is known to be sensitive to protamine, and heparin itself has been shown to cause thrombocytopenia in a subpopulation of patients undergoing open heart surgery. This is proposal to refine and develop an alternative to the heparin-protamine strategy. A novel device, termed clotting factor filter (CFF) has been developed that will bind and transiently remove clotting factors from circulating blood. Blood from which clotting factors have been removed would neither form clots nor thromboemboli during extracorporeal circulation, thus achieving the same effect as intended with heparin. Hypocoagulable blood gradually returns to normal state when the procedure is stopped, or recovery can be accelerated and normal hemostasis restored immediately by transfusion of autologous blood or plasma. Preliminary Phase I studies have confirmed the safety and efficacy of CFF approach. The objective of this Phase II proposal include: optimization of the CFF, characterization and performance of the optimized system, and verification that the CFF is able to effect appropriate 'anticoagulation' safely during cardiopulmonary bypass in an animal model. For the active matrix, linkers and base substrates will be investigated. For the plasma-matrix contact system, optimal column geometry will be selected, and a high-flow plasma separator will be designed. The optimal CFF system will be characterized to ascertain required level of 'anticoagulation' that will eliminate thrombosis during ECC. Finally, a porcine CPB model will be utilized to test the safety and efficacy of the CFF approach for 'anticoagulation' of blood during bypass. This will include careful assessment of hematologic and cardiovascular parameters during the procedure and during long term survival of the animal to assure that CFF approach is efficacious and safe.